Low-dose photodynamic therapy promotes a cytotoxic immunological response in a murine model of pleural mesothelioma

2020 ◽  
Vol 58 (4) ◽  
pp. 783-791
Author(s):  
Sabrina Cavin ◽  
Aspasia Gkasti ◽  
Julien Faget ◽  
Yameng Hao ◽  
Igor Letovanec ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Immune Checkpoint ◽  
Tumour Growth ◽  
Low Dose ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Pleural Mesothelioma ◽  
Tumour Control

Abstract OBJECTIVES Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Approaches to enhance patient immunity against MPM have been tested but shown variable results. Previously, we have demonstrated interesting vascular modulating properties of low-dose photodynamic therapy (L-PDT) on MPM. Here, we hypothesized that L-PDT vascular modulation could favour immune cell extravasation in MPM and improve tumour control in combination with immune checkpoint inhibitors. METHODS First, we assessed the impact of L-PDT on vascular endothelial E-selectin expression, a key molecule for immune cell extravasation, in vitro and in a syngeneic murine model of MPM. Second, we characterized the tumour immune cell infiltrate by 15-colour flow cytometry analysis 2 and 7 days after L-PDT treatment of the murine MPM model. Third, we determined how L-PDT combined with immune checkpoint inhibitor anti-CTLA4 affected tumour growth in a murine MPM model. RESULTS L-PDT significantly enhanced E-selectin expression by endothelial cells in vitro and in vivo. This correlated with increased CD8+ T cells and activated antigen-presenting cells (CD11b+ dendritic cells and macrophages) infiltration in MPM. Also, compared to anti-CTLA4 that only affects tumour growth, the combination of L-PDT with anti-CTLA4 caused complete MPM regression in 37.5% of animals. CONCLUSIONS L-PDT enhances E-selectin expression in the MPM endothelium, which favours immune infiltration of tumours. The combination of L-PDT with immune checkpoint inhibitor anti-CTLA4 allows best tumour control and regression.

scholarly journals Esophageal cancer responsive to the combination of immune cell therapy and low-dose nivolumab: two case reports

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Rishu Takimoto ◽  
Takashi Kamigaki ◽  
Takuji Gotoda ◽  
Toshimi Takahashi ◽  
Sachiko Okada ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Low Dose ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Chemoradiation Therapy ◽  
Advanced Esophageal Cancer

Abstract Background Blocking the programmed death 1 pathway by immune checkpoint inhibitors induces dramatic antitumor activity in patients with malignant tumors. However, the clinical response to immune checkpoint inhibitors remains limited owing to the patients’ immunological status, such as the number of lymphocytes, programmed death ligand 1 expression, and tumor mutation burden. In this study, we successfully treated two patients with advanced esophageal cancer who responded to the combination of adoptive immune cell therapy and a low-dose immune checkpoint inhibitor, nivolumab. Case presentation Two Asian (Japanese) patients with advanced esophageal cancer who were resistant to conventional chemoradiation therapy were referred to our hospital for immune therapy. Case 1 was a 66-year-old woman who was diagnosed as having esophageal cancer. She received concurrent chemoradiation therapy and then underwent subtotal esophagectomy, after which she became cancer free. However, she relapsed, and cancer cells were found in the lung and lymph nodes 6 months later. She enrolled in a clinical trial at our institution (clinical trial number UMIN000028756). She received adoptive immune cell therapy twice at a 2-week interval followed by low-dose nivolumab with adoptive immune cell therapy four times at 2-week intervals. A follow-up computed tomography scan showed partial response, with mass reduction of the metastatic lung and mediastinal lesions. Case 2 was a 77-year-old man. He received concurrent chemoradiation therapy with fluoropyrimidine/platinum, and gastroscopy revealed complete remission of esophageal cancer. He was disease free for 5 months, but routine computed tomography revealed multiple metastases in his lungs and lymph nodes. He visited our clinic to receive adoptive immune cell therapy and immune checkpoint inhibitor combination therapy. Radiographic evidence showed continuous improvement of lesions. There was no evidence of severe adverse events during the combination therapy. Conclusion The combination of adoptive immune cell therapy and an immune checkpoint inhibitor might be a possible treatment strategy for advanced esophageal cancer. Trial registration UMIN000028756. Registered 14 September 2017

KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3538-3538
Author(s):  
Ling Zhang ◽  
Jianping Song ◽  
Yiting Wang ◽  
Yaoxu Chen
Keyword(s):  
Colorectal Cancer ◽  
Survival Data ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Colon Adenocarcinoma ◽  
Treg Cells ◽  
Prognostic Effect

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.

scholarly journals Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingyu Chen ◽  
Haotian Chen ◽  
Dong He ◽  
Yaxin Cheng ◽  
Yuxing Zhu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Checkpoint Inhibitor ◽  
Clinical Prognosis

The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

scholarly journals Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics

2020 ◽  
Vol 117 (24) ◽  
pp. 13428-13436 ◽  
Author(s):  
Colin G. Buss ◽  
Sangeeta N. Bhatia
Keyword(s):  
Animal Models ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Engineered Nanoparticles ◽  
Therapeutic Effects

The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.

Outcomes in patients with advanced non-small cell lung cancer (aNSCLC) and high PD-L1 expression treated with immune checkpoint inhibitor monotherapy: An FDA-pooled analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9606-9606
Author(s):  
Sujay Yogesh Shah ◽  
Jonathon Joseph Vallejo ◽  
Yutao Gong ◽  
Thomas D. Brown ◽  
Chenan Zhang ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Cell Staining ◽  
Line Of Therapy ◽  
The Relationship

9606 Background: Higher PD-L1 score ≥ 50% predicts for greater benefit to immune checkpoint inhibitor (ICI) therapy in first line (1L) treatment of aNSCLC. It has recently been reported that PD-L1 score ≥ 90% predicts for even greater benefit to 1L ICI monotherapy (Aguilar et al., 2019). We examined pooled clinical trial databases to examine the relationship between high PD-L1 expression across multiple ICI monotherapies in 1L and second line (2L) treatment of aNSCLC. Methods: Data was pooled from trials (five 1L and five 2L) of ICI for the treatment of patients with aNSCLC. We defined PD-L1 score as the proportion of tumor cell stained by the assay (total of four assays identified) and included patients in the analysis with PD-L1 score ≥ 50%. Tumor-infiltrating immune cell staining was not considered. Progression-free survival (PFS) and overall survival (OS) by line of therapy for patients with PD-L1 score ≥ 90% and patients with PD-L1 score 50-89% was analyzed. Results: A total of 1320 patients treated with ICI monotherapy were identified, 873 in 1L and 447 in 2L. Median follow-up was 9.6 months in 2L patients and 13.3 months in 1L patients. Patients receiving 2L ICI therapy with PD-L1 score ≥ 90% (N = 208) had longer PFS and OS compared to patients with PD-L1 score 50-89% (N = 239), with mPFS 7.1 vs. 4.2 months (HR = 0.66 [95% CI: 0.52-0.83]) and mOS NR vs. 15.8 months (HR = 0.66 [95% CI: 0.49-0.89]). 1L ICI therapy analysis revealed similar trends, as patients with PD-L1 score ≥ 90% (N = 405) had longer PFS and OS compared to patients with a PD-L1 score 50-89% (N = 468), with mPFS 8.3 vs. 5.4 months (HR = 0.78 [95% CI: 0.66-0.92]) and mOS 22.9 vs. 16.4 months (HR = 0.74 [95% CI: 0.61-0.90]). Conclusions: This analysis showed the potential of an enhanced clinical benefit in patients with aNSCLC and PD-L1 score ≥90% across ICI monotherapies in both the 1L and 2L treatment setting. These data will be further analyzed in real world populations.

Using precision microbiome profiling to develop a biomarker for immune checkpoint inhibitor response and a novel therapeutic.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21546-e21546
Author(s):  
Mat Robinson ◽  
Kevin Vervier ◽  
Amy Popple ◽  
Simon Harris ◽  
Robyne Hudson ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
Metagenomic Sequencing ◽  
Genome Database ◽  
Syngeneic Mouse Model ◽  
Melanoma Patients

e21546 Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.

scholarly journals IMMU-21. THE COMBINATION OF DELTA-24-ACT WITH AN IMMUNE CHECKPOINT INHIBITOR RESULTS IN ANTI-GLIOMA EFFECT AND IMMUNE MEMORY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii109-ii109
Author(s):  
Montserrat Puigdelloses ◽  
Virginia Laspidea ◽  
Marc Garcia-Moure ◽  
Daniel De la Nava ◽  
Dolores Hambardzumyan ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Immune Memory ◽  
Long Term Survivors ◽  
Anti Tumour Effect ◽  
Murine Glioma

Abstract Oncolytic viruses have become promising therapeutic candidates to treat gliomas. Our group has developed Delta-24-ACT, an oncolytic adenovirus armed with the positive costimulatory ligand 4-1BBL which is capable to trigger the activation of T cells and thereby increase their antitumor immune response. Here we evaluate the anti-glioma effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor. We observed that Delta-24-ACT was able to infect and kill murine glioma (GL261-5 and CT-2A) and also human glioma cell lines (U87-MG and U251-MG), while maintaining its replication in the latter. Of importance, Delta-24-ACT infection resulted in 4-1BBL expression on the membrane of glioma cells. Moreover, this ligand was functional and was able to stimulate CD8 lymphocytes in vitro, suggesting the potential of Delta-24-ACT to trigger an effective immune response. Furthermore, in vivo Delta-24-ACT showed anti-tumour effect in two murine glioma models by significantly increasing the median survival time and leading to long-term survivors. Mechanistic studies demonstrated an increase of the T cell infiltration and the activation of different immune cell populations by flow cytometry and a decrease of proliferative cells and tumour vessels by immunohistochemistry on FFPE brain samples. Importantly, the infiltrating lymphocytes also showed signs of exhaustion increasing the amount of IL-10 and the expression of PD-1. To overcome this exhaustion we combined Delta-24-ACT with an anti-PD-1 antibody. Evaluation of this combination in vivo further increased the median survival time of treated tumor-bearing mice and resulted in 50% long-term survivors. Rechallenge studies with the same cell line showed that combination treatment effectively protected these animals of developing tumors and therefore, the acquisition of immune memory. In summary, our data demonstrated that Delta-24-ACT induces a potent anti-tumour effect in vitro and in vivo as a result of the recruitment of immune cell populations modulating the immunosuppressive tumour microenvironment of glioma.

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